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Biomedical subjects

A Fasth

Publications and source records attributed to A Fasth.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prenatal diagnosis of RAG-deficient Omenn syndrome.

Mutations in recombination activating genes (RAG) 1 and 2 have been found to cause Omenn syndrome (OS), a severe combined immunodeficiency (SCID) with a peculiar phenotype. Here we report the prenatal diagnosis performed in three OS patients. Mutations were detected in the probands as well as in their parents by genomic sequencing of the complete coding regions of both RAG 1 and RAG 2, which are contained in a single exon. All the three probands had RAG 1 mutations in both alleles, at least one of which was a missense substitution. Of the three fetuses tested, one had a wild type sequence on both alleles, while the other two had one mutated allele. None of the three patients were predicted to be affected and this was confirmed at birth. Detection of RAG genes mutations on fetal samples by direct sequencing is an easy and effective way to investigate fetuses from families affected with RAG-dependent SCID and OS families affected by RAG-dependent SCID and OS.

Amniocentesis↗
PubMed1999

[CATCH22 or 22q11 deletion syndrome. An underdiagnosed and misunderstood disease category with a variable clinical picture].

Patients with CATCH 22 or 22q11 deletion syndrome constitute a fast growing category in Sweden as it is still underdiagnosed. In a series of 54 patients the predominant features were found to be speech and language difficulties, cardiac malformations, susceptibility to infection, learning and behavioural problems, hypoparathyroidism, minor motor deficits, and characteristic facies. The severity of these problems varied individually, but as the patients had numerous symptoms and disabilities the overall degree of handicap was considerable. Thus, regular evaluation of the patient's condition and overall need of care is important.

Adolescent↗
PubMed1999

Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency.

We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (<6 months) and period during which BMT was performed. Better results were achieved after 1991. Reduced survival of patients with B- SCID was associated with a higher incidence of early deaths from infection, a diminished rate of marrow engraftment, a trend to a higher incidence of chronic graft-versus-host disease, and slower kinetics of T/B immune function development. In both groups of patients, the use of busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a conditioning regimen provided the best cure rate (74% for patients with B+ SCID and 43% for patients with B- SCID, respectively), although results were not statistically significantly different from other regimens. This retrospective analysis should lead to the design of adapted measures to the performance of HLA non-identical BMT in patients with distinct SCID conditions.

Age Factors↗
PubMed1999

Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation.

Osteopetrosis is a heterogeneous group of diseases characterized by lack of osteoclast function. Osteopetrosis is found spontaneously in most mammalian species and many transgenic animals have been created, but so far no animal model has been found that genetically corresponds to human malignant autosomal recessive osteopetrosis. The only curative treatment for malignant osteopetrosis is bone marrow transplantation. A review of the literature and preliminary data from IBMTR shows that infants transplanted with marrow from an HLA-identical sibling or unrelated volunteer donor have an actuarian five-year survival with a functioning graft of 50-70%, while those transplanted with a T-cell-depleted mismatched marrow have a very poor survival of only about 10%.

Animals↗
PubMed1999

Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis.

We have performed prenatal diagnosis for Wiskott Aldrich syndrome (WAS) in two unrelated families by direct gene analysis. Using a combined non-radioactive analysis of single-strand conformational polymorphism (SSCP) and heteroduplex formation (HD), followed by automated sequencing, we studied DNA from chorionic villus sampling (CVS), allowing the diagnosis of one affected and one healthy male at the 12th week of gestation.

Base Sequence↗
PubMed1998

Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.

We have performed a retrospective analysis of the development of T- and B-cell functions after HLA-nonidentical T-cell-depleted bone marrow transplantation (BMT) performed in 193 patients with severe combined immunodeficiency (SCID) at 18 European centers between December 1982 and December 31, 1993. One hundred sixteen of 193 patients were alive with evidence of engraftment 6 months after BMT. Development of T-cell function occurred earlier than B-cell function and was achieved more frequently up to the time of last follow-up. The median time to achieve normal T-cell function was 8.7 months, whereas the median time to achieve normal B-cell function was 14.9 months. Twenty-four patients died later than 6 months post-BMT, mainly due to chronic graft-versus-host disease (cGVHD) and/or viral infection. Absence of T-cell reconstitution 6 months after BMT, unlike absence of B-cell reconstitution, was associated with a poor outcome. Two additional factors were associated with a poor outcome: presence of cGVHD 6 months after BMT and B- SCID versus B+ SCID. However, two of these three factors remained as significant prognostic factors in a multivariate analysis: the absence of T-cell function and the presence of cGVHD 6 months after BMT. Analysis of the factors influencing the development of immune reconstitution showed that T- and B-cell functions occurred earlier and more frequently in B+ SCID versus B- SCID patients. Acute GVHD was associated with a slower development of T-cell function at 6 months, and cGVHD had a negative influence on the development of T-cell function afterwards, but neither acute nor chronic GVHD was found to influence the development of B-cell function. Once engraftment occurred, whether patients had or had not received Busulfan in the conditioning regimen did not influence the kinetics and quality of T-cell function development. In a multivariate study, two factors were found to influence the T-cell function 6 months after BMT: type of SCID and acute GVHD. The results of this retrospective analysis should lead to new protocols adapted to SCID disease, considering that disease-related as well as BMT-related parameters influence the development of immune function and thereby long-term outcome after HLA-nonidentical T-cell-depleted BMT.

B-Lymphocytes↗
PubMed1998

Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by eczema, thrombocytopenia, and immunodeficiency. An allelic variant of the disease is characterized by isolated thrombocytopenia (XLT). The gene responsible for WAS/XLT (WASP) encodes for a 502 amino acid protein (WASP) that is possibly involved in actin binding and cytoskeleton organization. The expression of WASP and the distribution of F-actin and alpha-actinin (which binds to and stabilizes actin filaments) have been analysed in lymphoblastoid cell lines from six patients with WAS and one with XLT. Western blot and immunocytochemistry did not reveal WASP expression in four WAS patients, whereas two WAS patients (with a moderate clinical course) expressed trace amounts of mutant WASP. In contrast, the XLT patient expressed normal amounts of WASP. Furthermore, cell lines from WAS and XLT patients also markedly differed in F-actin polymerization and alpha-actinin distribution. In particular, severe defects of cytoplasmic F-actin expression and of F-actin-positive microvillus formation, and impaired capping of alpha-actinin, were observed in all patients who lacked WASP. As a whole, the degree of impairment of WASP protein expression in WAS/XLT seems to correlate with anomalies of cytoskeletal organization, strongly supporting a role for WASP in the regulation of F-actin polymerization.

Actinin↗
PubMed1998

Anaphylactoid reactions and nephrotic syndrome--a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers.

Anaphylaxis/anaphylactoid reactions have recently been reported after few treatments with factor IX concentrates in patients with haemophilia B at the same time as inhibitors to factor IX were demonstrated. In some of these cases nephrotic syndrome has appeared during immune tolerance induction (ITI) with high doses of factor IX concentrates. Gene deletions seem to be associated with a high risk of developing antibodies to factor IX. This report presents two brothers with deletion of 1 bp in exon f of the factor IX gene. Both showed anaphylactoid reactions and they were desensitized using slow i.v. injections of factor IX. At the time of anaphylaxis, inhibitors of factor IX in a low titre could be demonstrated. The elder brother responded well after a short time on ITI and has no spontaneous bleedings on regular prophylaxis although in a somewhat higher dose than expected. On the other hand, in spite of comparable regimens, the younger brother has so far been resistant to ITI. Moreover, during treatment with extremely high doses of factor IX concentrate he developed nephrotic syndrome which only slowly subsided after treatment with corticosteroids and withdrawal of factor IX.

Anaphylaxis↗
PubMed1998

Juvenile chronic arthritis in urban San José, Costa Rica: a 2 year prospective study.

OBJECTIVE: To find the incidence and prevalence of juvenile chronic arthritis (JCA) in the urban area of San José, Costa Rica. METHODS: During the year preceding our 2 year prospective, population based study, we conducted an educational program on JCA. The physicians caring for children < 16 years of age from all centers in the study area followed the program. They were asked to refer all cases of possible JCA according to EULAR criteria. The children were all evaluated at the National Children's Hospital. RESULTS: Of 189 children referred, 48 fulfilled EULAR criteria for JCA. The 2 year incidence rate for JCA was 13.7 per 100,000 children < 16 years old. This corresponds to an annual incidence per 100,000 children of 6.8 (95% CI 4.1-9.6). The incidence rate for pauciarticular onset JCA was 3.9 per 100,000. At the prevalence date, 122 cases of JCA were recorded, corresponding to a prevalence of 34.9 per 100,000 children < 16 years. When patients in remission were excluded, the prevalence was 31.4 per 100,000 (95% CI 25.5-37.2). The pauciarticular onset form was the most common, 71% of all prevalence cases. The highest incidence and prevalence were noted for pauciarticular girls with late onset JCA. No incidence peak was found in preschool age. The girl-to-boy ratio was 1.5/1. Antinuclear antibodies (ANA) were positive in only 7 cases (6.3%). IgM rheumatoid factor was found in 13 children (10.6%). Chronic iritis was observed in 4 cases, all of them ANA negative and older than 7 years of age at onset of arthritis. CONCLUSION: The incidence and prevalence observed were lower than those reported in other population based studies, but within the confidence intervals of their data. The incidence rate for pauciarticular JCA was significantly lower than that reported in other comparable studies. ANA positive pauciarticular preschool girls and associated uveitis were rarely encountered.

Adolescent↗
PubMed1997

Clinical spectrum of X-linked hyper-IgM syndrome.

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Bone Marrow Transplantation↗
PubMed1997

Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibilty to AML.

Adolescent↗
PubMed1997

Development of a Costa Rican version of the Childhood Health Assessment Questionnaire.

OBJECTIVE: To validate a Spanish language version of the Childhood Health Assessment Questionnaire (CHAQ) for use in Costa Rica and to evaluate the feasibility, reliability, and cross cultural equivalency of this version. METHODS: The original questionnaire, translated without modification into Spanish, was administered to 12 children, all above 10 years of age, with the diagnosis of juvenile chronic arthritis (JCA) and to their parents. There were several problems in comprehension, and self-administration with this version was not possible. For this reason a teacher and a psychologist were consulted to create a modified Costa Rican version. We administered this 2nd version to 46 children with JCA and 62 of their parents. RESULTS: The modified Costa Rican HAQ (CR-CHAQ) was self-administered by 93.5% of the patients and 84% of the parents. The median time to complete the questionnaire was 12 min for the children, 10 min for the parents. The main difficulty in comprehension was the pain score for both groups. Test-retest (Spearman R = 0.73) and interobserver (Spearman R = 0.70) reliability were good. Validity of the instrument was confirmed by the high correlation between the disability and discomfort scores and conventional clinical variables. There was satisfactory correlation between the disability score and conventional clinical variables. Discriminant validity was confirmed by the capacity of the CR-CHAQ to evaluate patients as being in different categories of disease activity. CONCLUSION: After modifications, the CR-CHAQ achieved cross cultural equivalency.

Adolescent↗
PubMed1996

Intravenous immunoglobulin and hepatitis C virus: the Scandinavian experience.

In Sweden, 44 patients were reported to have contracted hepatitis C virus (HCV) infections from treatment with intravenous immunoglobulin. Gammagard was the product implicated in HCV transmission in 12 patients; 8 of these 12 patients were HCV ribonucleic acid (RNA)-negative during the 2 years before Gammagard was administered and 10 showed clustering by sequencing of the HCV core gene. Further studies are being conducted to correlate the sequenced HCV RNA with specific batches of Gammagard. Nine patients who received Gammonativ in 1983 and 1984 had a strong time-related possibility of HCV infection. Sequencing analyses are being performed in these patients as is being done for the patients who received Gammagard. Another 21 patients who received Gammonativ from 1982 to 1985 are probably infected with HCV, but confirmation of implicated batches is lacking. The association between Sandoglobulin and HCV is questionable in two patients, although plausible because of a time relationship. In Norway, relationships between Gammonativ and the incidence of HCV infection are similar to those in the 21 sporadic cases in Sweden. Also in Denmark and Finland, HCV infection appears to be related to the lack of additional viral inactivation steps used in the preparation of intravenous immunoglobulin. Clearly, there is a need for increased antiviral inactivation and antiviral screening in the production of intravenous immunoglobulin products.

Adult↗
PubMed1996

Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection.

OBJECTIVE: For children with life-threatening inborn errors of metabolism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without increasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte function-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency group with promising results. To optimize engraftment, and thereby survival, further, the additional blockade of a second important leukocyte adhesion and signalization pathway mediated by the CD2 and LFA-3 interaction was attempted in a multicenter protocol conducted by the European Bone Marrow Transplantation-European Society for Immunodeficiency group. Results of this study (ie, engraftment and survival) were compared with a historical control group that received the anti-LFA-1 antibody alone. Factors that may have affected engraftment and survival were also considered in this study. METHODS: Forty-four children with inborn errors, including inherited immunodeficiencies (excluding severe combined immunodeficiencies), Chédiak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unrelated donors at 13 European centers between August 1990 and June 1993. Bone marrow was depleted of T cells by use of either erythrocyte (E) rosetting or monoclonal antibodies (MoAbs) to prevent graft-versus-host disease. The conditioning regimen consisted of busulfan and cyclophosphamide for all patients plus etoposide for patients with osteopetrosis, familial hemophagocytic lymphohistiocytosis, and Chédiak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molecules were started 4 and 3 days, respectively, before and continued through the first 10 and 11 days, respectively, after bone marrow transplantation (a total of 14 injections). RESULTS: The overall sustained engraftment rate was 69.8%, with full chimerism in 80.6% of patients and no late graft rejection with the use of two MoAbs versus 65.7% and 58.1%, respectively, in the control group, in which only one MoAb was infused. The overall actuarial survival rate with a functional graft was 40.9%, with a mean follow-up of 39.3 months with two MoAbs versus 37.8% with one. The engraftment rate was significantly influenced by the T-cell depletion method, with better results for recipients of E rosette- depleted marrow (78.6% vs 20% for Campath 1-M plus complement-depleted marrows). Graft-versus-host disease and the kinetics of immune reconstitution were similar in both groups. CONCLUSIONS: The overall engraftment rate and overall survival rate with engraftment in patients treated with anti-LFA-1 and anti-CD2 were similar to those in patients treated with anti-LFA-1 antibody alone. However, although the number of patients is too small to draw definitive conclusions, results from the combined use of the two MoAbs indicates a trend toward better engraftment and survival after infusion of E rosette-depleted marrow. Further improvement in survival would demand additional strategies to hasten immunologic recovery.

Antibodies, Monoclonal↗
PubMed1996

Deep Candida infection in children receiving allogeneic bone marrow transplants: incidence, risk factors and diagnosis.

Fifty-eight children, who received 60 allogeneic bone marrow transplants (BMT), were studied with regard to incidence, risk factors and diagnosis of deep Candida infection (DCI). Serum samples were analysed for the presence of Candida IgA, IgM and IgG antibodies and free C. albicans glucoprotein antigen (Ag). Five children (8.7%) had a confirmed DCI and died before engraftment of the new bone marrow. When four patients with suspected deep Candida infection (SDCI) were included, the incidence was 15.6%. Four of the five children (80%) with DCI had pathological Candida IgM antibody (Ab) titers and/or free C. albicans glucoprotein Ag, 2-50 days before DCI was verified by culture, direct microscopy and/or autopsy. Risk factors, using Fisher's exact test for DCI, included not receiving bone marrow from an HLA-identical sibling donor, having a seropositive Herpes simplex virus (HSV) donor and pathological IgA and/or IgM Ab titers against Candida before BMT. In conclusion, a child with the above-mentioned risk factors, runs a risk of acquiring fatal DCI before engraftment. The institution of systemic antifungal prophylactic treatment may prevent death from DCI. After BMT, serological examinations may be of value in the early detection of DCI.

Adolescent↗
PubMed1996

Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders.

Busulphan pharmacokinetics were investigated in 20 children, who underwent bone marrow transplantation for either leukemia or inherited disorders. Busulphan (1.90-6.02 mg/kg/day) was administered orally as a single dose or twice daily. Busulphan kinetics were found to be linear within the studied range. Children with inherited disorders eliminated busulphan significantly faster after the first and the last dose with half-lives (t1/2) of 1.93 and 1.71 h, respectively compared to children with leukemia (3.16 and 2.70 h, respectively). The area under plasma concentration curves (AUCs, corrected for mg/kg) as an expression for the systemic exposure of busulphan were significantly higher in children with leukemia, 22.4 and 19.04 mumol/l.h (5527 and 4690 ng.h.ml-1) after the first and the last dose, respectively, compared to 11.2 and 8.2 mumol/l.h (2768 and 2029 ng.h.ml-1) found in children with inherited disorders. The present results confirm those reported by others, ie busulphan pharmacokinetics can be influenced by the underlying disease and its status. Our population pharmacokinetic analysis showed a negative correlation between the weight corrected clearance and the age in both groups of children. However, clearance was about 42% higher in children with inherited disorders compared to those with leukemia. To estimate AUC for the first dose, we evaluated a limited sampling model based on three concentrations (1, 3 and 6 h). A high correlation (r = 0.998, P < 0.0001, n = 40) between the estimated and the determined AUC was found. The present model is reliable and adequate for studying more patients, with a long-term follow-up combined with drug monitoring in correlation with drug efficacy and toxicity to define the optimal busulphan dosage required.

Administration, Oral↗
PubMed1995

High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X-chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.

Base Sequence↗